It is estimated that osteoarthritis (“OA”) affects about 50 million Americans. Osteoarthritis is a process that can occur in any joint where the articular cartilage diminishes in thickness as one ages. This process continues throughout one's life until all the articular cartilage is gone. Thereafter, in the case of osteoarthritic knee joints, weight applied on the knee results in bone on bone wear. In most cases this process is associated with gradual, increasing pain, to the point that any walking can be unbearable. Osteoarthritis of the knee may also be associated with night pain that can severely inhibit a normal sleep pattern.
Osteoarthritis of the knee is an almost ubiquitous condition in humans over the age of 60. Osteoarthritis of the knee does typically affect the medial tibiofemoral joint. Many people develop gradual degradation of the articular cartilage on the medial aspect of their knee, which results in their knees becoming progressively bowlegged or genu varum. Often the pain of the arthritis is felt along the medial side of the knee and specifically the proximal tibial plateau. MRI scanning often shows a hyperemic area just beneath the medial part of the knee joint in the metaphysis of the tibia. The knee joint consists of the medial and lateral femoral tibial compartments and the patella-femoral joint. Osteoarthritis can primarily impact any one of these areas or all three. It is known that the most common type is osteoarthritis of the medial tibial femoral joint.
The American Academy of Orthopedic Surgeons (“AAOS”) recommended treatments for osteoarthritis of the knee include the following: weight loss, gentle exercise, anti-inflammatory medications followed by total knee replacement. The AAOS does not recommend arthroscopic debridement or any hyaluronic acid products such as SYNVISC®, EUFLEXXA™, ORTHOVISC®, SUPARTZ™, or HYALGAN® for treating knee osteoarthritis. In the past, hundreds of thousands of knee arthroscopies were performed to lavage the knee with saline and debride frayed articular cartilage. This treatment has been shown in prospective randomized studies to have no efficacy and in fact often accelerates the degeneration of the articular cartilage. Four prospective randomized studies have shown no benefit over placebo at six-month follow-up with these hyaluronic acid injections. Despite the fact hyaluronic acid products have shown no efficacy, the market for these products is several hundred million dollars per year. One substantial reason for this may be the huge void between non-operative treatments and the only surgical treatment, total knee arthroplasty.
Last year in the United States over 900,000 total hip and knee replacements were performed with a direct cost of over $30 billion. These numbers are expected to double in the next three years. Additionally, it has been reported that every day 10,000 people in the United States turn 65 years of age, and that this will continue for the next 14 years.
OA has long been considered a “wear and tear” disease leading to loss of cartilage. OA used to be considered the sole consequence of any process leading to increased pressure on one particular joint or fragility of cartilage matrix. Progress in molecular biology in recent decades has profoundly modified this paradigm in favor of an “inflammatory” paradigm. Recent reports have shown that subchondral bone may have a substantial role in the OA process, as a mechanical damper, as well as a source of inflammatory mediators implicated in the OA pain process and in the degradation of the deep layer of cartilage. Thus, initially considered cartilage driven, OA is now considered to be a much more complex disease with inflammatory mediators released by cartilage, bone and synovium. Low-grade inflammation induced by the metabolic syndrome, innate immunity and inflammaging are some of the more recent arguments in favor of the inflammatory paradigm of OA. (See, Berenbaum, F., “Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!),” Osteoarthritis and Cartilage, 21:16-21 (2013)). (See also: Sokolove, J. et al., “Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations,” Ther Adv Musculoskel Dis, 5(2):77-94 (2013)).
Bone inflammation, also known as osteitis, is a condition that causes bone to become thickened or swollen. This increase in mass may result in bone distortion, such as bowing or arching of a straight long bone. When the bone begins to change shape, it can also produce pain by altering weight bearing positions or increasing pressure against other internal structures of the body.
To understand osteitis, it is important to understand the roles of inflammation and pain in the healing process. Inflammation is the body's natural response to fight off anything that compromises homeostasis, or internal balance. Swelling protects an area and calls on more blood to travel there to initiate the healing process. The accompanying pain symptoms are the body's warning system. Pain is also a protective mechanism to hinder excessive movements which may cause further injury.
When bone sustains an injury that disrupts normal function, such as a fracture, it increases the risk of infection. The body, in turn, may cause inflammation to help rid itself of invading contaminants. Osteomyelitis, for example, is a bone infection that causes inflammation. This infection travels through the blood to the inside of the bone and affects the marrow. The marrow, which consists of vascular tissue, is located in the middle of the bone and is responsible for creating new blood cells.
Periostitis occurs when the protective bone covering or periosteum is involved in the inflammatory process. This condition can occur with an infection process, or it may be triggered by excessive external pressure created by the surrounding muscles.
When there is damage to the joints that connect bones, as with arthritis conditions, bone inflammation and pain issues can occur. The arthritis common as part of the aging process is called osteoarthritis and affects the entire bone. It can cause destruction of the bone or produce abnormal ridges or projections. Osteoarthritis may also be activated by certain diseases.
Bones constantly regenerate by a process called bone remodeling. Paget's disease, which may also lead to osteoarthritis, is a health condition that disturbs normal bone remodeling. This can cause bones to form irregularly resulting in deformity, a loss of overall bone strength and inflammation.
Successful treatment of inflammation depends on treating the cause. If it is produced by an infection, symptoms will continue until the infection is eliminated. With health conditions that cause permanent damage to the joints or bones, a comprehensive exercise and strengthening program may help alleviate painful symptoms and may also aid in the restoration of range of motion. In severe cases, surgical correction of the bone may be necessary.
Mesenchymal stem cells (MSCs), after their initial discovery in bone marrow, have been isolated and characterized from several adult and fetal tissues, including adipose (fat), dermis (skin), synovial fluid, periosteum, umbilical cord blood, placenta and amniotic fluid. MSCs are partially defined by their ability to differentiate into tissues including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells). But it is believed that it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications. (See, Murphy, M. B., et al., “Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine,” Experimental & Molecular Medicine, 45:e54 (2013)).
The primary trophic property of MSCs is the secretion of growth factors and other chemokines to induce cell proliferation and angiogenesis. MSCs express mitogenic proteins such as transforming growth factor-alpha (TGF-α), TGF-β, hepatocyte growth factor (HGF), epithelial growth factor (EGF), basic fibroblast growth factor (FGF-2) and insulin-like growth factor-1 (IGF-1) to increase fibroblast, epithelial and endothelial cell division. Vascular endothelial growth factor (VEGF), IGF-1, EGF and angiopoietin-1 are released to recruit endothelial lineage cells and initiate vascularization. It has been hypothesized that an individual's genotype has a role in the expression of and reaction to these cytokines, providing credence to the philosophy of personalized medicine utilizing responsive agents (that is, MSCs) rather than a dose of recombinant proteins or autologous growth factors (for example, plateletrich plasma). The trophic effects extend beyond cell proliferation to the reduction of scar tissue formation presumably by local cells secreting paracrine factors keratinocyte growth factor, stromal cell-derived factor-1 (SDF-1) and macrophage inflammatory protein-1 alpha and beta.
MSCs have been reported to possess anti-inflammatory and immunomodulatory properties. In many types of musculoskeletal trauma, inflammatory conditions at the site of injury impede the natural repair processes by local progenitor and mature cells. Without being bound by theory, it is believed that MSCs assist via paracrine mechanisms and modulate the regenerative environment via anti-inflammatory and immunomodulatory mechanisms. In response to inflammatory molecules such as interleukin-1 (IL-1), IL-2, IL-12, tumor necrosis factor-α (TNF-α) and interferon-gamma (INF-γ), MSCs secrete an array of growth factors and anti-inflammatory proteins with complex feedback mechanisms among the many types of immune cells. The key immunomodulatory cytokines include prostaglandin 2, TGF-β1, HGF, SDF-1, nitrous oxide, indoleamine 2,3-dioxygenase, IL-4, IL-6, IL-10, IL-1 receptor antagonist and soluble tumor necrosis factor-α receptor. MSCs prevent proliferation and function of many inflammatory immune cells, including T cells, natural killer cells, B cells, monocytes, macrophages and dendritic cells. Although MSCs across species are able to regulate T-cell activity, the mechanisms are not identical across mammalian species.
A characteristic of chronically inflamed environments is a persistent imbalance in the types of helper T cells and macrophages. MSCs indirectly promote the transition of TH1 to TH2 cells by reducing INF-g and increasing IL-4 and IL-10. The restored TH1/TH2 balance has been shown to improve tissue regeneration in cartilage, muscle and other soft tissue injuries, alleviate symptoms of autoimmune diseases and have an anti-diabetic effect. Similarly, reduction in INF-γ and secretion of IL-4 promotes a shift in macrophages from M1 (pro-inflammatory, anti-angiogenic and tissue growth inhibition) to M2 (anti-inflammatory, pro-remodeling and tissue healing) type, an effect required for skeletal, muscular and neural healing and regeneration. (See, Murphy, M. B., et al., “Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine,” Experimental & Molecular Medicine, 45:e54 (2013)).
The foregoing cited publications, and all other publications cited throughout this application, are incorporated herein by reference in their entirety.